Insuliln-like growth factor (IGF-1) is a 70 amino acid single polypeptide chain factor which displays relatively-high homology with proinsulin. IGF-1 is known to have a mediating effect on the action of growth hormone and also to display insulin-like properties. When produced in nature by the human body, IGF-1 is unglycosylated.
IGF-1 has potential uses as a pharmaceutical agent both in the treatment of pituitary dwarfism and also diabetes. In the latter case it would be useful either as a replacement for insulin or as an adjunct to insulin. Although insulin is the traditional treatment for diabetes, type-2 diabetics have developed a resistance to insulin which means that even if very high doses of insulin are administered, the patients can still suffer from hyperglycemia. Further, excessive doses of insulin can lead to undesirable side effects such as kidney complaints, obesity, and a disturbed water balance.
Although unglycosylated IGF-1 could be used as a replacement or adjunct for insulin in an attempt to overcome some of these problems, a high proportion of unglycosylated IGF-1 tends to be sequestrated by specific binding proteins circulating in the bloodstream. Therefore, relatively high doses of the IGF-1 need to be administered for the desired pharmaceutical effect to be attained.
We have now discovered that expression of IGF-1 in yeast cells results in the production, along with the normal unglycosylated form, of an O-glycosylated analog of IGF-1, for example, an analog which carries two mannose residues on the Thr .sub.29 amino acid of the polypeptide chain. Tests have shown that O-glycosylated IGF-1 has a reduced affinity for the binding proteins and that a desired reduction in blood sugar level can be achieved by a reduced dose of O-glycosylated IGF-1 as compared with the normal unglycosylated protein. This observed affinity for the binding protein will have a profound effect on the profile and dose dependency. The other effects, although not so pronounced are of importance in the total clinical effect.
The expression "O-glycosylated IGF-1" embraces O-glycosylated molecules which comprise fragments of the whole IGF-1 polypeptide sequence, provided that those fragments display qualitatively the growth-hormone mediating effect and/or insulin-like properties of IGF-1.